KR100446711B1 - Novel non-peptide compounds having bradykinin antagonistic activity, preparation thereof and their pharmaceutical composition - Google Patents

Abstract

The present invention relates to a novel non-peptidyl compound having bradykinin antagonism, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

The novel compounds of the present invention have a structure of formula (1), and R ¹ and R ² of formula (1) have a structure as defined herein.

The method for preparing a compound of the present invention uses a liquid combinatorial chemical method.

Pharmaceutical compositions comprising the compound of the present invention as an active ingredient are useful as a prophylactic and therapeutic agent for various diseases mediated by bradykinin.

Description

Novel non-peptide compounds having bradykinin antagonistic activity, preparations and their pharmaceutical compositions

The present invention relates to a novel non-peptidyl compound having bradykinin antagonism, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

Bradykinin is an endogenous peptide hormone consisting of nine amino acids and is produced from the precursor kininogen by a group of proteolytic enzymes called kallikrein.

Bradykinin is secreted by inflammation, trauma, burns, shock, allergies, and certain cardiovascular diseases, and once secreted initiates or increases the secretion of mediators that stimulate the nociceptive afferent nerve endings from white blood cells. The various pathophysiological reactions caused by bradykinin include septic shock, hemorrhagic shock, hypersensitivity, arthritis, rhinitis, asthma, inflammatory bowel disease, acute pancreatitis, gastric resection, carcinoidosis, migraine, hereditary Angioedema.

The receptors of bradykinin are classified mainly into B1 and B2 types according to the efficacy of various bradykinin analogs.

The action of bradykinin at the B1 receptor mainly involves contracting arteries and veins, but may also relax peripheral resistance vessels. However, many of the more important functions of bradykinin, such as increased vascular permeability, pain and vasodilation, are modulated by B2 receptors. Since bradykinin at the B2 receptor causes hypotension and inflammation and increases capillary permeability, leading to edema and pain, it is known to play an important role in many diseases such as inflammation, cardiovascular disease, pain and colds.

Therefore, the antagonist of the B1 receptor is useful as a drug having antipyretic and anti-inflammatory action, and the antagonist of the B2 receptor may be usefully used for asthma, allergic rhinitis, cold, inflammatory joint disease, pancreatitis, cystitis and the like.

The first generation antagonist for bradykinin is a peptide antagonist, mainly replacing proline at position 7 of the amino acid sequence of bradykinin with D-phenylalanine or D-aromatic amino acid, a representative substance known as NPC-349 D-Arg- [Hyp ³ , Thi ^5,8 , D-Phe ⁷ ] BK [Vaverk, RJ; Sewart, JM Competitive antagonists of bradykinin. Peptides 1985, 6, 161-164].

Developed as second generation antagonists are Icatibant (HOE 140) and Bradycor (CP0127, dimeric peptide) [Griesbacher, T .; Lembeck, F .; Eckhardt, M .; Henke, St .; Breipohl, G .; Knolle, J. New, long-acting, potent bradykinin antagonists. Br. J. Pharmacol . 1991, 102, 257-304 .; Hock, FJ; Wirth, K .; Albus, U .; Linz, W .; Gerhard, HJ; Weimer, G .; Henke, S .; Breiphl, G .; Konig, W .; Knolle, J .; Scholkens, BA Hoe 140, a new potent and long acting bradykinin-antagonist: in vitro studies . Br. J. Pharmacol . 1991, 102, 769-773 .; Wirth, K .; Albus, U .; Linz, W .; Alpermann, HJ; Anagnostopoulos, H .; Henke, S .; Breiphl, G .; Konig, W .; Knolle, J .; Scholkens, BA Hoe 140, a new potent and long acting bradykinin-antagonist: In vivo studies. Br. J. Pharmacol . 1991, 102, 774-777. They have a stronger affinity for the B2 receptor than the first generation antagonists and have a longer response duration in vivo but have lower bioavailability when administered orally, so their therapeutic use is still limited.

Recently, many studies have been conducted to develop drugs capable of long-term oral administration and treatment of chronic inflammatory diseases as non-peptide antagonists of bradykinin receptors.

The most representative examples of non-peptide antagonists of the B2 receptor are the phosphonium derivative WIN 64338 and the hetero aryl benzyl ether FR 173657 [Salvino, JM; Seoane, PR; Douty, BD; Awad, MMA; Dolle, RE; Houck, WT; Faunce, DM; Sawutz, DG Design of potent non-peptide competitive antagonist of the human bradykinin B2 receptor. J. Med. Chem . 1993, 36, 2583-2584, Abe, Y .; Kayakiri, H .: Satoh, S .; Inoue, T .; Sawada, Y .; Inamura, N .; Asanno, M .; Hatori, C .; Oku, T .; Tanaka, H. A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the Imidazo [1,2-a] pyridine moiety . J. Med. Chem. 1998, 41, 4062-4079.

In addition, the B2 receptor antagonistic effect was weakly observed in some compounds of the second generation antihistamines having piperazine residues. Among them, it was observed that the carbon side chain of cetirizine was transformed into an aryl or alkyl chain to exhibit antihistamine and anti-bradykinin action.

Therefore, it is expected to develop drugs having excellent bradykinin antagonism among compounds having piperazine residues.

It is an object of the present invention to provide a novel non-peptidyl compound having bradykinin antagonism, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient.

1 is a view showing a method for preparing a library of a compound of the present invention using a liquid combinatorial chemistry method.

2 is a view showing a method for preparing individual substances of the compound of the present invention using a liquid combinatorial chemical method.

Figure 3 is a diagram showing the accumulation-response curves for bradykinin according to the concentration change of pM4S3 of the present invention in the guinea pig ileum.

Figure 4 is a diagram showing the accumulation-response curves for bradykinin according to the concentration change of pM3S3 of the present invention in the guinea pig ileum.

5 is a diagram showing the accumulation concentration-response curve for bradykinin according to the concentration change of pM6-H of the present invention in guinea pig ileum.

FIG. 6 is a graph showing accumulation-response curves for bradykinin according to the concentration change of Hoe 140 as a control group in guinea pig ileum.

The present invention provides a novel non-peptidyl compound having bradykinin antagonism, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient.

The novel compounds of the present invention have the structure of formula (1) and include pharmaceutically acceptable salts of the compounds.

In Formula 1, R ¹ is isopropyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 1-methyl-3-phenylpropyl, 3,4,5-trimethoxybenzyl, 2- (4- (4 -Chlorophenyl) thiazole), 3- (5-t-butylisoxazole), 2- (4- (4-bromophenyl) thiazole), cyclohexyl, 5- (3-methylisoxazole), 3 , 4-dibenzyloxyphenethyl, R ² is H, R ³ CO, and R ³ represents methyl, phenyl, benzyl, naphthyl (C ₁₀ H ₇ ), C ₁₀ H ₇ CH ₂ .

Compounds of the present invention are prepared using liquid-phase combinatorial chemistry.

The compound of the present invention is prepared by using a liquid combinatorial chemistry method of dividing the structure of the target compound, such as the compound represented by Formula 1, into three parts and combining different substituents to each other.

Hereinafter, the manufacturing method of the present invention will be described in detail.

To prepare the compound represented by Formula 1, 50 libraries were prepared by using iminodiiacetic anhydride as a template and 12 amines, 1- (4-chlorobenzhydryl) piperazine, and 5 carboxylic acids. (FIG. 1, FIG. 2).

The template imino diacetic acid anhydride is a cyclic anhydride consisting of six atoms, represented by the following formula (2). Iminodiacetic anhydride is a symmetric structure in which three sites react in succession with three different functional groups to synthesize a library.

In Formula 2, P represents an amino protecting group, and may be selected from benzyl, benzyloxycarbonyl and t-butyloxycarbonyl group, and t-butyloxycarbonyl group is preferable.

The 12 amines used for reaction with iminodiacetic anhydride are isopropylamine, benzylamine, 4-methylbenzylamine, 4-methoxybenzylamine, 1-methyl-3-phenylpropylamine, 3,4,5- Trimethoxybenzylamine, 2- (4- (4-chlorophenyl) thiazole) amine, 3- (5-t-butylisoxazole) amine, 2- (4- (4-bromophenyl) thiazole) Amines, cyclohexylamine, 5- (3-methylisoxazole) amine, 3,4-dibenzyloxyphenethylamine.

Five carboxylic acids used for reaction with imino diacetic anhydride and amines are acetic acid, benzoic acid, phenylacetic acid, 2-naphthoic acid and 2-naphthyl acetic acid.

Specific preparation method for preparing a compound represented by Formula 1 of the present invention is the same as in Scheme 1.

In iminodiacetic acid, nitrogen is protected by t-butyloxycarbonyl (Boc) groups and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (EDCI) by in-situ reaction. ) To form the iminodiacetic anhydride template. The iminodiacetic anhydride template is reacted with amines to activate the first functional group of the iminodiacetic anhydride to open the ring. This results in a compound with a mono carboxylic acid remaining at the second activation site. To this compound, reaction with 1- (4-chlorobenzhydryl) piperazine using benzotriazol-1-yl-oxy-trispyrrolidino phosphonium hexafluorophosphate (PyBOP) as a binder, The compound to which the functional group is bound is produced. When hydrochloric acid-dioxane is reacted to remove the protecting group bound to nitrogen, and when combined with five carboxylic acids using bromotrispyrrolidino phosphonium hexafluorophosphate (PyBrOP) as a binder, three Libraries to which functional groups are bound are obtained. However, only the compound of formula 1 substituted with two amines, namely 5- (3-methylisoxazole) amine and 3,4-dibenzyloxyphenethylamine, will not react with the third functional group due to low reactivity.

In the present invention, a total of 50 libraries are prepared. In each step, each intermediate and final product is separated and purified from the starting materials, reactants, reagents and byproducts by liquid-liquid extraction known in the art.

The present invention provides a pharmaceutical composition for bradykinin antagonist containing one or more novel compounds of the present invention as an active ingredient.

The pharmaceutical composition of the present invention prevents or treats various symptoms caused by bradykinin by administering to a patient in need of bradykinin antagonistic effect. Therefore, the composition of the present invention can prevent or treat asthma, allergic rhinitis, arthritis, shock, rheumatoid arthritis, brain edema, angioedema, acute pancreatitis and the like caused by bradykinin.

The bradykinin antagonistic effect of each library and deconvolution of Compound 1 prepared in the present invention, guinea-pig guinea-pig according to the concentration change of the compound (0.03 u M ~ 1.0 u M) ileum smooth muscle).

The maximum response of bradykinin appears at about 1 u M and the reaction curve drops below that concentration.

The composition of the present invention comprises a pharmaceutically acceptable carrier and the dosage of the composition of the present invention comprises 5 to 250 mg, preferably 8 to 60 mg of the compound of the present invention per dose depending on the route of administration. do. Appropriate concentrations and doses can be determined by one skilled in the art.

Pharmaceutically acceptable carriers are well known to those skilled in the art. Acceptable carriers for compositions formulated into liquid solutions include saline and sterile water, and antioxidants, buffers, bacteriostatics, and other conventional additives may be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants may be added to the compositions of the present invention to formulate into pills, capsules, granules, or tablets. One of ordinary skill in the art can formulate the compounds of the present invention in an appropriate manner or in a recognized manner as described in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example 1 : Preparation of Novel Compounds Having Non-peptidyl Bradykinin Antagonism

1. Preparation of N-((t-butyloxy) carbonyl) iminodiacetic acid

Into a 1 L flask was placed imino diacetic acid (13.3 g, 100 mmol), dioxane (200 mL) and sodium hydroxide (8 g, 200 mmol) dissolved in 200 mL of water and stirred until the solution became uniform. A small amount of di-t-butyldicarbonate (25 mL, 110 mmol) was added to the solution, stirred at room temperature for 72 hours, and then the reaction mixture was washed with ether (2 x 100 mL). The aqueous layer was acidified with 10% hydrochloric acid (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with saturated brine (2 × 150 mL), water was removed with Na ₂ SO ₄ , and then recrystallized (ethyl acetate: hexane = 1: 2) to obtain colorless crystals.

Yield: 10.33 g (44%)

¹ H-NMR (Acetone-d ₆ , 400 MHz): 4.12 and 4.08 (two s, 4H), 1.4 (s, 9H)

2. Preparation of a compound in which an amine is bonded to the first functional group of N-((t-butyloxy) carbonyl) iminodiacetic acid

2a. Preparation of Compounds M2 to M6, M10

2a-1) Preparation of N-((t-butyloxy) carbonyl) -N'-benzyliminodiacetic acid monoamide (M2)

Into the flask, 6.4 ml of DMF dissolved in N-((t-butyloxy) carbonyl) iminodiacetic acid (0.5 g, 2.13 mmol) and EDCI (0.408 g, 2.13 mmol) prepared in 1 above was added. Stirred for 1 h. Benzylamine (0.23 g, 2.13 mmol) was slowly added dropwise thereto through a syringe, followed by stirring at room temperature for 20 hours. Dilute the reaction with ethyl acetate (60 mL), wash with 10% aqueous hydrochloric acid solution (2 × 40 mL), saturated brine (40 mL), remove moisture with Na ₂ SO ₄ , and remove the solvent under reduced pressure. To give a pale white solid.

Yield: 0.52 g (75%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2 (5H, m), 4.4 (2H, t), 4.0 (2H, d), 3.9 (2H, d), 1.3 and 1.4 (9H, two s )

FABMS m / z : 323.15

2a-2) Preparation of N-((t-butyloxy) carbonyl) -N '-(4-methylbenzyl) iminodiacetic acid monoamide (M3)

Yield: 0.49 g (68%), off-white oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2 (4H, m), 4.4 (2H, t), 3.9 and 4.0 (4H, two s), 2.3 (3H, s), 1.3 and 1.5 (9H , two s)

FABMS m / z : 337.18

2a-3) Preparation of N-((t-butyloxy) carbonyl) -N '-(4-methoxybenzyl) iminodiacetic acid monoamide (M4)

Yield: 0.43 g (55%), off-white oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 6.8 (2H, dt), 7.2 and 7.3 (2H, t), 4.4 (2H, d), 4.2 (2H, d), 4.0 (2H, d) , 3.8 (3H, s), 1.4 (9H, two s)

FABMS m / z : 353.16

2a-4) Preparation of N-((t-butyloxy) carbonyl) -N '-(1-methyl-3-phenylpropyl) iminodiacetic acid monoamide (M5)

Yield: 0.62 g (80%), white solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2 and 7.3 (5H, m), 4.1 (1H, m), 3.8-4.0 (4H, m), 2.6 (2H, q), 1.8 (2H, q), 1.4 (9H, d), 1.2 (3H, d)

FABMS m / z : 365.21

2a-5) Preparation of N-((t-butyloxy) carbonyl) -N '-(3,4,5-trimethoxybenzyl) iminodiacetic acid monoamide (M6)

Yield: 0.23 g (26%), off-white oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 6.5 (2H, d), 4.4 (2H, two d), 4.0 (4H, d), 3.8 (9H, two d), 1.4 (9H, s)

FABMS m / z : 413.18

2a-6) Preparation of N-((t-butyloxy) carbonyl) -N'-cyclohexylminodioacetic acid monoamide (M10)

Yield: 0.3 g (12%), white solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 4.0 (4H, dd), 3.8 (1H, m), 1.8 ~ 1.9 (2H, t), 1.7 (2H, m), 1.6 (1H, m) , 1.4 (9H, m), 1.2 ~ 1.3 (5H, m)

FABMS m / z : 315.02

2b. Preparation of Compounds M1, M12

2b-1) Preparation of N-((t-butyloxy) carbonyl) -N'-isopropyliminodiacetic acid monoamide (M1)

Into the flask, 6.4 ml of DMF dissolved in N-((t-butyloxy) carbonyl) iminodiacetic acid (0.5 g, 2.13 mmol) and EDCI (0.408 g, 2.13 mmol) prepared in 1 was added. Stir at 1 ° C. for 1 h. Isopropylamine (0.126 g, 2.13 mmol) was slowly added dropwise thereto via a syringe, and then reacted in the same manner as in 2a to obtain a light purple solid.

Yield: 0.3 g (53%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 3.9 (4H, dd), 2.6 (1H, s), 1.3 (9H, s), 1.0 (6H, dd)

FABMS m / z : 275.15

2b-2) Preparation of N-((t-butyloxy) carbonyl) -N '-(3,4-dibenzyloxyphenethyl) iminodiacetic acid monoamide (M12)

Yield: 0.51 g (44%), light white solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 6.6 ~ 7.4 (13H, m), 5.0 (4H, m), 3.9 (4H, m), 3.3 (2H, q), 2.6 (2H, m) , 1.3 (9H, d)

FABMS m / z : 549.25

2c. Preparation of Compounds M7-M9, M11

2c-1) Preparation of N-((t-butyloxy) carbonyl) -N '-(2- (4- (4-chlorophenyl) thiazole)) iminodiacetic acid monoamide (M7)

Into the flask, 6.4 ml of DMF dissolved in N-((t-butyloxy) carbonyl) iminodiacetic acid (0.5 g, 2.13 mmol) and EDCI (0.408 g, 2.13 mmol) prepared in 1 above was added. Stirred for 1 h. 2-amino-4- (4-chlorophenyl) thiazole (0.45 g, 2.13 mmol) and DMAP (0.52 g, 4.26 mmol) were slowly added dropwise thereto, followed by reaction in the same manner as 2a above to give yellow A solid was obtained.

Yield: 0.29 g (32%)

¹ H-NMR (Acetone-d ₆ , 400 MHz): 8.0 (2H, d), 7.5 (2H, d), 7.4 (1H, s), 3.9 (2H, d), 3.7 (2H, d), 1.3 (9H, s)

FABMS m / z : 426.08

2c-2) Preparation of N-((t-butyloxy) carbonyl) -N '-(3- (5-t-butylisoxazole)) iminodiacetic acid monoamide (M8)

Yield: 0.2 g (26%), white solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 6.2 (1H, s), 4.5 (4H, s), 1.5 (9H, s), 1.35 (9H, s)

FABMS m / z : 356.17

2c-3) Preparation of N-((t-butyloxy) carbonyl) -N '-(2- (4- (4-bromophenyl) thiazole)) iminodiacetic acid monoamide (M9)

Yield: 0.27 g (27%), reddish brown solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.7 (2H, d), 7.6 (1H, s), 7.5 (2H, d), 4.6 (4H, s), 1.4 (9H, s)

FABMS m / z : 480.03

2c-4) Preparation of N-((t-butyloxy) carbonyl) -N '-(5- (3-methylisoxazole)) iminodiacetic acid monoamide (M11)

Yield: 0.12 g (18%), light brown solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 6.2 (1H, s), 4.5 (4H, s), 2.4 (3H, s), 1.5 (9H, s)

FABMS m / z : 314.07

3. Preparation of compounds pM1 to pM12 in which 1- (4-chlorobenzhydryl) piperazine was bound to the compounds (M1 to M12) prepared in 2 above

3-1) N-((t-butyloxy) carbonyl) -N '-(1-methyl-3-phenylpropyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid dia Preparation of mead (pM5)

In a 30 ml vial N-((t-butyloxy) carbonyl) -iminodiacetic monoamide (M5, 0.48 g, 1.31 mmol, 1.0 eq.), 1- (4-chlorobenzhydryl) piperazine ( 0.41 g, 1.441 mmol, 1.1 eq.), Benzotriazol-1-yl-oxy-trispyrrolidino phosphonium hexafluorophosphate (PyBOP) 0.75 g (1.44 mmol, 1.1 eq.) , DMF (15 mL), N, N-diisopropylethylamine (i-Pr ₂ NEt; 0.5 mL, 2.62 mmol, 2.0eq.) Were added, followed by stirring at room temperature for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with 10% aqueous hydrochloric acid solution (100 mL), saturated aqueous NaHCO ₃ solution (2 x 50 mL), saturated brine (50 mL), and washed with Na ₂ SO ₄ . After removal, the solvent was removed under reduced pressure to obtain an off-white solid.

Yield: 0.78 g (94%)

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.1-7.5 (14H, m), 4.4 (1H, d), 4.2-4.3 (2H, m), 3.9 (1H, m), 3.7-3.8 ( 2H, m), 3.5-3.7 (4H, m), 2.5-2.7 (2H, m), 2.3-2.5 (4H, m), 1.7 (2H, m), 1.4 (9H, d), 1.0-1.2 ( 3H, dd)

FABMS m / z : 633.31

3-2) Preparation of N-((t-butyloxy) carbonyl) -N'-isopropyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM1)

Yield: 0.47 g (77%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.5 (9H, m). 4.4 (1H, s), 4.3 (2H, m), 3.95 (1H, s), 3.8-3.9 (4H, d), 3.6-3.7 (2H, m), 1.4 (9H, s), 1.3 (6H, s)

FABMS m / z : 543.02

3-3) Preparation of N-((t-butyloxy) carbonyl) -N'-benzyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM2)

Yield: 0.61 g (73%), orange solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.5 (14H, m), 4.4 (3H, ds), 4.2 (2H, d), 3.8 (2H, d), 3.6 (4H, s) , 2.4 (4H, m), 1.4 (9H, d)

FABMS m / z : 591.27

3-4) N-((t-butyloxy) carbonyl) -N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM3) Manufacture

Yield: 0.73 g (86%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.0-7.6 (13H, m), 4.4 (1H, s), 4.3 (2H, d), 4.2 (2H, d), 3.8 (2H, d) , 3.6 (4H, m), 2.4 (4H, m), 2.3 (3H, s), 1.3 (9H, d)

FABMS m / z : 605.21

3-5) N-((t-butyloxy) carbonyl) -N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM4 Manufacturing

Yield: 0.67 g (89%), orange solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (11H, m), 6.8 (2H, t), 4.4 (1H, s), 4.3 (2H, d), 4.2 (2H, d) , 3.8 (2H, d), 3.7 (3H, s), 3.6 (4H, m), 2.4 (4H, m), 1.4 (9H, d)

FABMS m / z : 621.28

3-6) N-((t-butyloxy) carbonyl) -N '-(3,4,5-trimethoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodi Preparation of Acetic Acid Diamide (pM6)

Yield: 0.31 g (81%), off-white solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.5 (9H, m), 6.6 (2H, d), 4.4 (1H, d), 4.3 (2H, d), 4.2 (2H, d) , 4.1 (2H, d), 3.8 (9H, d), 3.6 (4H, d), 2.4 (4H, d), 1.3 (9H, d)

FABMS m / z : 681.30

3-7) N-((t-butyloxy) carbonyl) -N '-(2- (4- (4-chlorophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) Preparation of Piperazine Iminodiacetic Diamide (pM7)

Yield: 0.34 g (69%), off-white solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-8.0 (14H, m), 4.45 (1H, s), 4.4 (2H, d), 4.1-4.15 (2H, d), 3.6-3.8 ( 4H, m), 2.4 (4H, m), 1.3-1.4 (9H, d)

FABMS m / z : 694.19

3-8) N-((t-butyloxy) carbonyl) -N '-(3- (5-t-butylisoxazole))-N "-1- (4-chlorobenzhydryl) piperazin imi Preparation of Nodiacetic Acid Diamide (pM8)

Yield: 0.29 g (83%), off-white solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.6 (9H, m), 6.6 (1H, d), 4.4 (1H, s), 4.3 (2H, d), 3.9-4.0 (2H, d), 3.5-3.7 (4H, m), 2.4 (4H, m), 1.3-1.4 (9H, d), 1.25 (9H, d)

FABMS m / z : 694.29

3-9) N-((t-butyloxy) carbonyl) -N '-(2- (4- (4-bromophenyl) thiazole))-N "-1- (4-chlorobenzhydryl Preparation of piperazine imino diacetic acid diamide (pM9)

Yield: 0.23 g (92%), off-white solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.9 (14H, m), 4.45 (1H, s), 4.4 (2H, d), 4.1-4.15 (2H, d), 3.4-3.6 ( 4H, m), 2.4 (4H, m), 1.3-1.4 (9H, d)

FABMS m / z : 738.14

3-10) Preparation of N-((t-butyloxy) carbonyl) -N'-cyclohexyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM10)

Yield: 0.47 g (65%), off-white solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.9 (14H, m), 4.45 (1H, s), 4.4 (2H, d), 4.0 (4H, dd), 3.8 (1H, s) , 3.4-3.6 (4H, m), 1.9-1.8 (2H, s), 1.7 (2H, m), 1.6 (1H, m), 1.5 (9H, m), 1.4-1.2 (5H, m)

FABMS m / z : 583.16

3-11) N-((t-butyloxy) carbonyl) -N '-(5- (3-methylisoxazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid Preparation of Diamide (pM11)

Yield: 0.09 g (82%), off-white solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (9H, m), 6.2 (1H, d), 4.5 (4H, s), 4.4 (2H, d), 4.0 (2H, d) , 3.6-3.8 (4H, m), 2.4 (4H, m), 2.2 (3H, d), 1.3-1.4 (9H, d)

FABMS m / z : 582.35

3-12) N-((t-butyloxy) carbonyl) -N '-(3.4-dibenzyloxyphenethyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide Preparation of (pM12)

Yield: 0.52 g (63%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-7.6 (9H, m), 7.2 (10H, m), 6.5 (3H, m), 5.2 (4H, d), 4.5 (4H, S) , 4.4 (2H, m), 3.9 (2H, m), 3.7-3.8 (4H, d), 3.5 (2H, s), 2.8 (2H, s), 1.4 (9H, S)

FABMS m / z : 817.37

4. Preparation of compounds pM2-H to pM12-H from which the N-protecting groups of the compounds (pM1 to pM12) prepared in 3 above were prepared, and preparation of compounds pM2S1 to pM10S5 in which these compounds were combined with carboxylic acids (S1 to S5)

4a: Preparation of the Compounds pM2-H to pM12-H

4a-1) Preparation of N- (4-methoxybenzyl) -N'-1- (4-chlorobenzylhydryl) piperazine iminodiisacetic acid diamide (pM4-H)

Chloroform (1 mL), 4M hydrochloric acid-dioxane (1 mL), and pM4 (0.033 g, 0.0538 mmol) prepared in 3 above were added to a 4 mL vial and stirred for 3 hours. Solvent and excess acid were evaporated off to give a yellow solid.

Yield: 20 mg (67%)

Melting Point (mp): 110-120 ℃

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (11H, m), 6.8 (2H, t), 4.4 (1H, s), 4.3 (2H, d), 4.2 (2H, d) , 3.8 (2H, d), 3.7 (3H, s), 3.6 (4H, m), 2.4 (4H, m)

FABMS m / z : 505.02

4a-2) Preparation of N-benzyl-N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM2-H)

Yield: 21 mg (99%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.5 (14H, m), 4.4 (3H, ds), 4.2 (2H, d), 3.8 (2H, d), 3.6 (4H, s) , 2.4 (4H, m)

FABMS m / z : 491.00

4a-3) Preparation of N- (4-methylbenzyl) -N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM3-H)

Yield: 6 mg (96%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.0-7.6 (13H, m), 4.4 (1H, s), 4.3 (2H, d), 4.2 (2H, d), 3.8 (2H, d) , 3.6 (4H, m), 2.4 (4H, m), 2.3 (3H, s)

FABMS m / z : 505.02

4a-4) Preparation of N- (1-methyl-3-phenyl) -N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM5-H)

Yield: 30 mg (100%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.1-7.5 (14H, m), 4.4 (1H, d), 4.2-4.3 (2H, m), 3.9 (1H, m), 3.7-3.8 ( 2H, m), 3.5-3.7 (4H, m), 2.5-2.7 (2H, m), 2.3-2.5 (4H, m), 1.7 (2H, m), 1.0-1.2 (3H, dd)

FABMS m / z : 533.01

4a-5) Preparation of N- (3,4,5-trimethoxybenzyl) -N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic diamide (pM6-H)

Yield: 58 mg (54%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.4-7.6 (9H, m), 6.6 (2H, d), 4.4 (1H, d), 4.3 (2H, d), 4.2 (2H, d) , 4.1 (2H, d), 3.8 (9H, d), 3.6 (4H, d), 2.4 (4H, d)

FABMS m / z : 581.30

4a-6) Preparation of N- (3- (5-t-butylisoxazole))-N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic diamide (pM8-H)

Yield: 13 mg (98%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.6 (9H, m), 6.6 (1H, d), 4.4 (1H, s), 4.3 (2H, d), 3.9-4.0 (2H, d), 3.5-3.7 (4H, m), 2.4 (4H, m), 1.25 (9H, d)

FABMS m / z : 524.06

4a-7) Preparation of N-cyclohexyl-N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM10-H)

Yield: 160 mg (66%), yellow solid

Melting Point (mp): 135-145 ℃

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.9 (14H, m), 4.45 (1H, s), 4.4 (2H, d), 4.0 (4H, dd), 3.8 (1H, s) , 3.4-3.6 (4H, m), 1.9-1.8 (2H, s), 1.7 (2H, m), 1.6 (1H, m), 1.4-1.2 (5H, m)

FABMS m / z : 483.01

4a-8) Preparation of N- (5- (3-methylisoxazole))-N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic diamide (pM11-H)

Yield: 16 mg (99%), brown solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (9H, m), 6.2 (1H, d), 4.5 (4H, s), 4.4 (2H, d), 4.0 (2H, d) , 3.6-3.8 (4H, m), 2.4 (4H, m), 2.2 (3H, d)

FABMS m / z : 481.95

4a-9) Preparation of N- (3,4-dibenzyloxyphenethyl) -N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide (pM12-H)

Yield: 7 mg (99%), yellow solid

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-7.6 (9H, m), 7.2 (10H, m), 6.5 (3H, m), 5.2 (4H, d), 4.5 (4H, S) , 4.4 (2H, m), 3.9 (2H, m), 3.7-3.8 (4H, d), 3.5 (2H, s), 2.8 (2H, s)

FABMS m / z : 717.0

4b: Preparation of a Sub Library in which the Carboxylic Acid (S1-5) was Reacted with the Compounds (pM1 to pM12) Prepared in 3 above

4b-1) Preparation of sublibrary pM2S1-5

A carboxylic acid stock solution was prepared by mixing 0.1858 mmol of each carboxylic acid (S1-S5) in 9 ml of a mixture of DMF / chloroform (8: 1).

Chloroform (1 ml), 4M hydrochloric acid-dioxane (1 ml), and pM2 (0.1 g, 0.169 mmol) prepared in 3 above were added to a 4 ml vial and stirred for 3 hours. Solvent and excess acid were removed by evaporation, the residue was dissolved in 1 mL of DMF, i-Pr ₂ NEt (0.53 mL, 3.09 mmol) was added, and then 0.1 mL (0.0103 mmol) of the carboxylic acid stock solution. And bromotrispyrrolidino phosphonium hexafluorophosphate (PyBrOP) 79.7 mg (0.169 mmol) were added and stirred for 16 hours. After stirring, the reaction mixture was diluted with ethyl acetate (90 mL), washed with 10% aqueous hydrochloric acid solution (3 x 90 mL), saturated aqueous NaHCO ₃ solution (2 x 90 mL), and saturated brine (90 mL). Water was removed with Na ₂ SO ₄ , and concentrated to give a reddish brown oil of the sub library.

Yield: 20 mg (20%)

FABMS m / z : 533.26, 595.367, 609.305, 645.32, 659.38

4b-2) Preparation of sublibrary pM1S1-5

Yield: 33 mg (35%), yellow oil

FABMS m / z : 485.12, 547.119, 561.11, 597.11, 611.11

4b-3) Preparation of sublibrary pM3S1-5

Yield: 11 mg (10%), orange oil

FABMS m / z : 547.31, 609.25, 623.34, 659, 673.31

4b-4) Preparation of sublibrary pM4S1-5

Yield: 30 mg (25%), orange oil

FABMS m / z : 563, 625.19, 639.15, 675, 689.2

4b-5) Preparation of sublibrary pM5S1-5

Yield: 41 mg (34%), yellow oil

FABMS m / z : 575.20, 637.20, 651.28, 687.26, 701.28

4b-6) Preparation of sublibrary pM6S1-5

Yield: 26 mg (20%), orange oil

FABMS m / z : 623.18, 685.21, 699.21, 735.24, 749.24

4b-7) Preparation of sub library pM7S1-5

Yield: 26 mg (20%), reddish brown oil

FABMS m / z : 636.18, 698.17, 712.2, 748.20, 762.25

4b-8) Preparation of sublibrary pM8S1-5

Yield: 35 mg (30%), yellow oil

FABMS m / z : 566, 628.09, 642, 678, 692.14

4b-9) Preparation of sublibrary pM9S1-5

Yield: 112 mg (82%), light brown oil

FABMS m / z : 680.04, 742, 756, 792.14, 806.11

4b-10) Preparation of sublibrary pM10S1-5

Yield: 18 mg (1%), yellow oil

FABMS m / z : 525.29, 587.26, 601.32, 6.37.30, 651.32

4c: Preparation of the Compounds pM2S1 to pM10S1, wherein the carboxylic acid (S1) was reacted with the compound (pM1 to pM12) prepared in 3 above

4c-1) Preparation of N-acetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM4S1)

Chloroform (1 mL), 4M hydrochloric acid-dioxane (1 mL), and pM4 (9.19 mg, 0.017 mmol) prepared in 3 above were added to a 4 mL vial and stirred for 3 hours. Solvent and excess acid were removed by evaporation, the residue was taken up in 1 ml of DMF, i-Pr ₂ NEt (9 μl, 0.051 mmol) was added, and then 0.001 g (0.019 mmol, 1.1 eq.) Of acetic acid (S1). ), PyBrOP 8.7 mg (0.019 mmol) was added and stirred for 16 hours. After stirring, the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% aqueous hydrochloric acid solution (3 x 30 mL), saturated NaHCO ₃ aqueous solution (2 x 30 mL), and saturated brine (30 mL). Water was removed with Na ₂ SO ₄ , and concentrated to give a brownish yellow oil.

Yield: 11.9 mg (71%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.1-7.5 (11H, m), 6.8-6.9 (2H, m), 4.4 (1H, d), 4.3 (2H, m), 4.1-4.2 ( 2H, m), 3.8 (2H, d), 3.7-3.8 (3H, m), 3.6 (4H, m), 2.3 (4H, m), 1.9 (3H, m)

FABMS m / z : 563.05

4c-2) Preparation of N-acetyl-N'-benzyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM2S1)

Yield: 1 mg (2%), white powder

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.5 (14H, m), 4.4 (3H, ds), 4.2 (2H, d), 3.8 (2H, d), 3.6 (4H, s) , 2.4 (4H, m), 2.0 (3H, s)

FABMS m / z : 533.02

4c-3) Preparation of N-acetyl-N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM3S1)

Yield: 58 mg (64%), reddish brown powder

Melting Point (mp): 100-110 ℃

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.0-7.5 (13H, m), 4.5 (1H, s), 4.3-4.4 (2H, t), 4.3 (2H, m), 4.0 (2H, d), 3.6 (4H, m), 2.3-2.4 (4H, m), 2.1 (3H, s), 2.0 (3H, d)

FABMS m / z : 547.10

HRFABMS m / z : 547.2475

4c-4) Preparation of N-acetyl-N '-(1-methyl-3-phenylpropyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM5S1)

Yield: 23 mg (76%), reddish brown oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.1-7.5 (14H, m), 4.4-4.5 (1H, d), 4.2-4.3 (2H, d), 4.0-4.2 (1H, m), 3.9-4.0 (2H, m), 3.6 (4H, m), 2.5-2.7 (2H, m), 2.3-2.5 (4H, m), 2.0 (3H, d) 1.6-1.8 (2H, m), 1.0 -1.1 (3H, dd)

FABMS m / z : 575.05

4c-5) Preparation of N-acetyl-N '-(3,4,5-trimethoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM6S1)

Yield: 7.3 mg (33%), brownish yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (9H, m), 6.6 (2H, m), 4.4 (1H, d), 4.3 (2H, d), 4.2 (2H, d) , 4.1 (2H, d), 3.8 (9H, m), 3.7 (4H, m), 2.4 (4H, m), 2.2 (3H, m)

FABMS m / z : 623.14

4c-6) N-acetyl-N '-(2- (4- (4-chlorophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM7S1 Manufacturing

Yield: 10.0 mg (13%), light yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.0-7.7 (14H, m), 4.22 (1H, s), 4.2 (2H, d), 4.1-4.15 (2H, d), 3.5-3.8 ( 4H, m), 2.4 (4H, m), 2.0 (3H, m)

FABMS m / z : 635.96

4c-7) Preparation of N-acetyl-N '-(3- (5-t-butylisoxazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM8S1)

Yield: 20.0 mg (17%), light yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.5 (9H, m), 6.6 (1H, d), 4.6 (1H, s), 4.4 (2H, d), 4.0-4.3 (2H, d), 3.5-3.7 (4H, m), 2.5 (4H, m), 2.4 (3H, m)

FABMS m / z : 566.02

4c-8) N-acetyl-N '-(2- (4- (4-bromophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide ( Preparation of pM9S1)

Yield: 40.0 mg (20%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.9 (14H, m), 4.45 (1H, s), 4.4 (2H, d), 4.1-4.15 (2H, d), 3.4-3.6 ( 4H, m), 2.4 (4H, m), 2.0 (3H, s)

FABMS m / z : 679.92

4c-9) Preparation of N-acetyl-N'-cyclohexyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM10S1)

Yield: 10.0 mg (30%), white powder

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.9 (14H, m), 4.45 (1H, s), 4.4 (2H, d), 4.0 (4H, dd), 3.8 (1H, s) , 3.4-3.6 (4H, m), 2.0 (3H, s) 1.9-1.8 (2H, s), 1.7 (2H, m), 1.6 (1H, m)

FABMS m / z : 525

4d: Preparation of the compounds pM2S2 to pM10S2 by reacting the carboxylic acid (S2) with the compound (pM1 to pM12) prepared in 3 above

4d-1) Preparation of N-benzoyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM4S2)

Into a 4 mL vial was added chloroform (1 mL), 4M hydrochloric acid-dioxane (1 mL), 26.5 mg (0.049 mmol) of pM4 prepared in 3 above, and stirred for 3 hours. Solvent and excess acid were removed by evaporation, the residue was taken up in 1 ml of DMF and 0.026 ml (0.15 mmol) of i-Pr ₂ NEt was added followed by 6.6 mg (0.054 mmol, 1.1 eq.) Of benzoic acid (S2). ), PyBrOP 25 mg (0.054 mmol) was added and stirred for 16 hours. After stirring, the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% aqueous hydrochloric acid solution (3 x 30 mL), saturated aqueous NaHCO ₃ solution (2 x 30 mL), and saturated brine (30 mL). Water was removed with Na ₂ SO ₄ and concentrated to give a reddish brown oil.

Yield: 9 mg (53%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.1-7.5 (11H, m), 6.8 (2H, t), 4.4 (1H, d), 4.3 (2H, m), 4.1-4.2 (2H, m), 3.8 (2H, d), 3.7-3.8 (3H, m), 3.6 (4H, m), 2.3 (4H, m)

FABMS m / z : 655.08

4d-2) Preparation of N-benzoyl-N'-4-benzyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM2S2)

Yield: 7 mg (14%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.8 (19H, m), 4.4 (3H, ds), 4.2 (2H, d), 3.8 (2H, d), 3.6 (4H, s) , 2.4 (4H, m)

FABMS m / z : 595.20

4d-3) Preparation of N-benzoyl-N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM3S2)

Yield: 67 mg (66%), red oil

Melting Point (mp): 98-118 ℃

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.1-7.5 (18H, m), 4.4 (1H, s), 4.3-4.4 (2H, m), 4.0-4.1 (2H, m), 3.6 ( 2H, m), 3.3-3.5 (4H, s), 2.3 (4H, d), 2.0-2.2 (3H, m)

FABMS m / z : 609.1

HRFABMS m / z : 609.2630

4d-4) Preparation of N-benzoyl-N '-(1-methyl-3-phenylpropyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM5S2)

Yield: 37 mg (77%), yellow oil

Melting Point (mp): 92-105 ℃

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.4-7.8 (5H, m) 7.1-7.4 (14H, m), 4.4 (1H, d), 4.2-4.3 (2H, m), 3.9 (1H , m), 3.7-3.8 (2H, m), 3.5-3.7 (4H, m), 2.5-2.7 (2H, m), 2.3-2.5 (4H, m), 1.7 (2H, m), 1.0-1.2 (3H, dd)

FABMS m / z : 637.03

4d-5) Preparation of N-benzoyl-N '-(3,4,5-trimethoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM6S2)

Yield: 5 mg (21%), reddish yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.4-7.7 (5H, m), 7.2-7.4 (9H, m), 6.6 (2H, d), 4.4 (1H, d), 4.3 (2H, d), 4.2 (2H, d), 4.1 (2H, s), 3.8 (9H, d), 3.6 (4H, d), 2.2-2.5 (4H, d)

FABMS m / z : 707.06

4d-6) N-benzoyl-N '-(2- (4- (4-chlorophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM7S2 Manufacturing

Yield: 35.0 mg (53%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-8.0 (19H, m), 4.45 (1H, s), 4.4 (2H, d), 4.1-4.15 (2H, d), 3.6-3.8 ( 4H, m), 2.4 (4H, m)

FABMS m / z : 698.03

4d-7) Preparation of N-benzoyl-N '-(3- (5-t-butylisoxazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM8S2)

Yield: 40.0 mg (27%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 8.0-8.2 (5H, m) 7.2-7.7 (9H, m), 6.6 (1H, s), 4.5-4.6 (1H, s), 4.2-4.5 (2H, d), 4.1-4.2 (2H, d), 3.4-3.7 (4H, d), 1.3 (4H, m)

FABMS m / z : 628.16

4d-8) N-benzoyl-N '-(2- (4- (4-bromophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide ( Preparation of pM9S2)

Yield: 40.0 mg (21%), light yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.9 (19H, m), 4.45 (1H, s), 4.4 (2H, d), 4.1-4.15 (2H, d), 3.4-3.6 ( 4H, m), 2.4 (4H, m)

FABMS m / z : 741.95

4d-9) Preparation of N-benzoyl-N'-cyclohexyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM10S2)

Yield: 35 mg (95%), brownish yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-8.1 (19H, m), 4.45 (1H, s), 4.4 (2H, d), 4.0 (4H, dd), 3.8 (1H, s) , 3.4-3.6 (4H, m), 1.9-1.8 (2H, s), 1.7 (2H, m), 1.6 (1H, m), 1.4-1.2 (5H, m)

FABMS m / z : 586

4e: Preparation of the compounds pM2S3 to pM10S3 by reacting the carboxylic acid (S3) with the compound (pM1 to pM12) prepared in 3 above

4e-1) Preparation of N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM4S3)

Into a 4 mL vial was added chloroform (1 mL), 4M hydrochloric acid-dioxane (1 mL), and 0.031 g (0.050 mmol) of pM4 prepared in 3 above, followed by stirring for 3 hours. Solvent and excess acid was removed by evaporation, the residue was dissolved in 1 mL of DMF, 26.1 μl (0.15 mmol) of i-Pr ₂ NEt was added, and then 7.49 mg (0.055 mmol, 1.1 eq.) Of phenylacetic acid (S3). ), PyBrOP 25.64 mg (0.055 mmol) was added and stirred for 16 hours. After stirring, the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% aqueous hydrochloric acid solution (3 x 30 mL), saturated aqueous NaHCO ₃ solution (2 x 30 mL), and saturated brine (30 mL). Water was removed with Na ₂ SO ₄ and concentrated to give a brownish yellow oil.

Yield: 25 mg (77%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (11H, m), 7.0-7.2 (5H, m) 6.8 (2H, t), 4.4 (1H, s), 4.3 (2H, d ), 4.2 (2H, d), 3.8 (2H, d), 3.7 (3H, s), 3.6 (4H, m), 3.4 (2H, s), 2.4 (4H, m)

FABMS m / z : 639.10

4e-2) Preparation of N-phenylacetyl-N'-benzyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM2S3)

Yield: 6 mg (17%), light yellow powder

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.5 (14H, m), 7.0-7.2 (5H, m), 4.4 (3H, ds), 4.2 (2H, d), 3.8 (2H, d), 3.6 (4H, s), 3.4 (2H, s), 2.4 (4H, m)

FABMS m / z : 609.21

4e-3) Preparation of N-phenylacetyl-N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM3S3)

Yield: 77 mg (74%), reddish brown powder

Melting Point (mp): 98-105 ℃

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.5 (13H, m), 7.1-7.2 (5H, m), 4.6 (1H, s), 4.4 (2H, d), 4.0-4.1 ( 2H, d), 3.65 (2H, s), 3.6 (4H, m), 2.8 (2H, d), 2.3-2.4 (4H, m), 2.3 (3H, s)

FABMS m / z : 623.30

HRFABMS m / z : 623.2786

4e-4) Preparation of N-phenylacetyl-N '-(1-methyl-3-phenylpropyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM5S3)

Yield: 14 mg (34%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.1-7.5 (14H, m), 7.1-7.2 (5H, m), 4.4 (1H, d), 4.2-4.3 (2H, m), 3.9 ( 1H, m), 3.7-3.8 (2H, m), 3.5-3.7 (4H, m), 3.4 (2H, s), 2.5-2.7 (2H, m), 2.3-2.5 (4H, m), 1.7 ( 2H, m), 1.0-1.2 (3H, dd)

FABMS m / z : 651.15

4e-5) Preparation of N-phenylacetyl-N '-(3,4,5-trimethoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM6S3)

Yield: 2 mg (9%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-7.6 (9H, m), 7.2 (5H, m), 6.6 (2H, d), 4.6 (1H, s), 4.4 (2H, d) , 4.3 (2H, m), 4.0-4.1 (2H, d), 3.7-3.8 (9H, d), 3.6 (6H, m), 2.3-2.4 (4H, m)

FABMS m / z : 699.1

4e-6) N-phenylacetyl-N '-(2- (4- (4-chlorophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide ( Preparation of pM7S3)

Yield: 80 mg (99%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-8.0 (14H, m), 7.0-7.2 (5H, m), 4.45 (1H, s), 4.4 (2H, d), 4.1-4.15 ( 2H, d), 3.6-3.8 (4H, m), 3.4 (2H, s), 2.4 (4H, m)

FABMS m / z : 711.95

4e-7) N-phenylacetyl-N '-(3- (5-t-butylisoxazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM8S3) Produce

Yield: 44 mg (32%), reddish brown oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.55 (9H, m), 7.2 (5H, m), 6.6 (1H, t), 4.65 (1H, s), 4.3-4.4 (2H, q), 3.8-4.1 (2H, m), 3.6-3.7 (6H, m), 2.4-2.5 (4H, m)

FABMS m / z : 642.14

4e-8) N-phenylacetyl-N '-(2- (4- (4-bromophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide Preparation of (pM9S3)

Yield: 50 mg (23%), reddish brown oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.2-7.7 (14H, m), 7.0-7.2 (5H, m), 4.05-4.2 (5H, m), 3.6-3.7 (4H, m), 3.45 (2H, t), 2.4 (4H, q)

FABMS m / z : 755.98

4e-9) Preparation of N-phenylacetyl-N'-cyclohexyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM10S3)

Yield: 10 mg (26%), light yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.3-7.7 (14H, m), 7.2-7.3 (5H, m), 4.45 (1H, t), 4.3 (2H, s), 4.0-4.3 ( 4H, m), 3.6-3.7 (4H, m), 3.3 (2H, d), 1.7 (2H, m), 1.6 (2H, m), 1.2-1.4 (5H, m)

FABMS m / z : 601.00

4f: Preparation of the compounds pM2S4 to pM10S4 by reacting the carboxylic acid (S4) with the compound (pM1 to pM12) prepared in 3 above

4f-1) Preparation of N- (2-naphthoyl) -N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM4S4)

Chloroform (1 mL), 4M hydrochloric acid-dioxane (1 mL), and 0.035 g (0.056 mmol) of pM4 prepared in 3 above were added to a 4 mL vial, followed by stirring for 3 hours. Solvent and excess acid was removed by evaporation, the residue was dissolved in 1 mL of DMF, 29.3 μl (0.168 mmol) of i-Pr ₂ NEt was added, and 10.68 mg (0.062 mmol, 2-naphthoic acid (S4) was added. 1.1eq.) And 28.9 mg (0.062 mmol) of PyBrOP were added and stirred for 16 hours. After stirring, the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% aqueous hydrochloric acid solution (3 x 30 mL), saturated aqueous NaHCO ₃ solution (2 x 30 mL), and saturated brine (30 mL). Water was removed with Na ₂ SO ₄ and concentrated to give a reddish brown oil.

Yield: 29 mg (77%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-8.0 (18H, m) 6.8 (2H, t), 4.4 (1H, s), 4.3 (2H, d), 4.2 (2H, d), 3.8 (2H, d), 3.7 (3H, s), 3.6 (4H, m), 2.4 (4H, m)

FABMS m / z : 575.24

4f-2) Preparation of N- (2-naphthoyl) -N'-benzyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM2S4)

Yield: 8 mg (19%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-8.0 (21H, m), 4.4 (3H, ds), 4.2 (2H, d), 3.8 (2H, d), 3.6 (4H, s) , 2.4 (4H, m)

FABMS m / z : 645.2

4f-3) Preparation of N- (2-naphthoyl) -N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM3S4)

Yield: 93 mg (85%), red powder

Melting Point (mp): 105-120 ℃

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.1-8.0 (20H, m), 4.5 (1H, s), 4.0-4.2 (2H, m), 3.6-3.7 (2H, m), 3.2- 3.5 (4H, m), 2.3-2.5 (4H, q), 1.8-2.1 (3H, m)

FABMS m / z : 659.15

HRFABMS m / z : 659.2787

4f-4) N- (2-naphthoyl) -N '-(1-methyl-3-phenylpropyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM5S4) Manufacture

Yield: 43 mg (97%), reddish brown oil

Melting Point (mp): 100-134 ℃

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.0-8.0 (21H, m), 4.4 (1H, d), 4.2-4.3 (2H, m), 3.9 (1H, m), 3.7-3.8 ( 2H, m), 3.5-3.7 (4H, m), 2.5-2.7 (2H, m), 2.3-2.5 (4H, m), 1.7 (2H, m), 1.0-1.2 (3H, dd)

FABMS m / z : 687.15

4f-5) N- (2-naphthoyl) -N '-(3,4,5-trimethoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide ( Preparation of pM6S4)

Yield: 4 mg (14%), white powder

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-8.1 (16H, m), 6.7 (2H, d), 4.5 (1H, s), 4.45 (2H, d), 4.4 (2H, d) , 4.05 (2H, m), 3.75 (9H, d), 3.6 (4H, s), 2.4-2.5 (4H, d)

FABMS m / z : 735.22

4f-6) N- (2-naphthoyl) -N '-(2- (4- (4-chlorophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodi Preparation of Acetic Acid Triamide (pM7S4)

Yield: 60 mg (61%), yellowish brown oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.0-8.0 (21H, m), 4.2-4.3 (5H, m), 3.4-3.8 (4H, m), 1.8-2.0 (4H, m)

FABMS m / z : 748.03

4f-7) N- (2-naphthoyl) -N '-(3- (5-t-butylisoxazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide Preparation of (pM8S4)

Yield: 40 mg (25%), white oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-8.0 (16H, m), 6.6 (1H, d), 4.4 (1H, s), 4.3 (2H, d), 3.9-4.0 (2H, d), 3.5-3.7 (4H, m), 2.4 (4H, m)

FABMS m / z : 678.00

4f-8) N- (2-naphthoyl) -N '-(2- (4- (4-bromophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazin imi Preparation of Nodiacetic Acid Triamide (pM9S4)

Yield: 40 mg (21%), brownish yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.4-8.0 (21H, m), 4.0-4.4 (5H, m), 3.4-3.8 (4H, m), 2.4 (4H, d)

FABMS m / z : 791.92

4f-9) Preparation of N- (2-naphthoyl) -N'-cyclohexyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM10S4)

Yield: 80 mg (34%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-8.0 (21H, m), 4.45 (1H, s), 4.4 (2H, d), 4.0 (4H, dd), 3.8 (1H, s) , 3.4-3.6 (4H, m), 1.9-1.8 (2H, s), 1.7 (2H, m), 1.6 (1H, m), 1.4-1.2 (5H, m)

FABMS m / z : 637.28

4g: Preparation of the compounds pM2S5 to pM10S5 by reacting the carboxylic acid (S5) with the compound (pM1 to pM12) prepared in 3 above

4g-1) Preparation of N- (2-naphthylacetyl) -N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM4S5)

Chloroform (1 mL), 4M hydrochloric acid-dioxane (1 mL), and 0.036 g (0.058 mmol) of pM4 prepared in 3 above were added to a 4 mL vial and stirred for 3 hours. Solvent and excess acid was removed by evaporation, the residue was dissolved in 1 mL of DMF, 30.3 μl (0.174 mmol) of i-Pr ₂ NEt was added, followed by 11.9 mg (0.064 mmol, 2-naphthylacetic acid (S5) 1.1eq.) And PyBrOP 29.84 mg (0.064 mmol) were added and stirred for 16 hours. After stirring, the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% aqueous hydrochloric acid solution (3 x 40 mL), saturated aqueous NaHCO ₃ solution (2 x 40 mL), and saturated brine (30 mL). Water was removed with Na ₂ SO ₄ and concentrated to give a brownish yellow oil.

Yield: 34 mg (84%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.1-7.9 (18H, m), 6.8-6.9 (2H, m), 4.5 (1H, s), 4.2 (2H, t), 3.9-4.0 ( 2H, m), 3.75 (2H, d), 3.7 (3H, d), 3.4 (4H, m), 3.3 (2H, s), 2.3 (4H, m)

FABMS m / z : 689.01

4g-2) Preparation of N- (2-naphthylacetyl) -N'-benzyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM2S5)

Yield: 8 mg (25%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.5 (21H, m), 4.4 (3H, ds), 4.2 (2H, d), 3.8 (2H, d), 3.6 (4H, s) , 3.5 (2H, s), 2.4 (4H, m)

FABMS m / z : 659.2

4g-3) Preparation of N- (2-naphthylacetyl) -N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM3S5)

Yield: 91 mg (82%), red powder

Melting Point (mp): 95-116 ℃

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.1-7.9 (20H, m), 4.4 (1H, d), 4.3-4.4 (2H, m), 4.0-4.2 (2H, d), 3.8 ( 2H, s), 3.5-3.6 (4H, m), 3.1 (2H, m), 2.8 (4H, d), 2.3-2.4 (4H, m)

FABMS m / z : 673.21

HRFABMS m / z : 673.2943

4g-4) N- (2-naphthylacetyl) -N '-(1-methyl-3-phenylpropyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM5S5 Manufacturing

Yield: 40 mg (90%), yellow oil

Melting Point (mp): 85-103 ℃

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.0-7.7 (21H, m), 4.4 (1H, d), 4.2-4.3 (2H, m), 3.9 (1H, m), 3.7-3.8 ( 2H, m), 3.4-3.7 (4H, m), 3.5 (2H, s), 2.5-2.7 (2H, m), 2.3-2.5 (4H, m), 1.7 (2H, m), 1.0-1.2 ( 3H, dd)

FABMS m / z : 701.13

4g-5) N- (2-naphthylacetyl) -N '-(3,4,5-trimethoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide Preparation of (pM6S5)

Yield: 10 mg (39%), light yellow powder

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.9 (16H, m), 6.6 (2H, d), 4.65 (1H, s), 4.4 (2H, d), 4.3 (2H, q) , 4.0-4.2 (2H, d), 3.7-3.8 (9H, m), 3.7 (2H, m), 3.5-3.6 (4H, m), 2.3-2.4 (4H, m)

FABMS m / z : 771.18

4g-6) N- (2-naphthylacetyl) -N '-(2- (4- (4-chlorophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine imidine Preparation of Nodiacetic Acid Triamide (pM7S5)

Yield: 60 mg (47%), yellow oil

¹ H-NMR (Acetone-d ₆ , 400 MHz): 7.0-7.8 (21H, m), 4.2 (1H, s), 4.15 (2H, d), 3.7-3.8 (4H, m), 3.4-3.5 ( 2H, dt), 2.1-2.4 (4H, m)

FABMS m / z : 762.11

4g-7) N- (2-naphthylacetyl) -N '-(3- (5-t-butylisoxazole))-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid tria Preparation of mead (pM8S5)

Yield: 44 mg (32%), light yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.9 (16H, m), 6.6 (1H, d), 4.7 (1H, s), 4.4 (2H, t), 4.1-4.0 (2H, d), 3.9-4.0 (4H, m), 3.8-3.9 (2H, s), 1.9 (4H, s)

FABMS m / z : 692.10

4g-8) N- (2-naphthylacetyl) -N '-(2- (4- (4-bromophenyl) thiazole))-N "-1- (4-chlorobenzhydryl) piperazine Preparation of IminoDiacetic Acid Triamide (pM9S5)

Yield: 60 mg (22%), reddish yellow oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.3-8.0 (21H, m), 4.7 (1H, s), 4.4-4.6 (2H, q), 4.2-4.3 (2H, d), 3.6- 4.1 (4H, m), 3.5 (2H, m), 3.3 (4H, d)

FABMS m / z : 805.82

4g-9) Preparation of N- (2-naphthylacetyl) -N'-cyclohexyl-N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide (pM10S5)

Yield: 6 mg (13%), reddish brown oil

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.9 (21H, m), 4.45 (1H, s), 4.4 (2H, d), 4.0 (4H, dd), 3.8 (1H, s) , 3.5 (2H, s), 3.4-3.5 (4H, m), 1.9-1.8 (2H, s), 1.7 (2H, m), 1.6 (1H, m), 1.4-1.2 (5H, m)

FABMS m / z : 651.02

Example 2 : Active Test of Each Library

Activity tests of each library were performed using guinea-pig ileum.

250-600 g of male Hartley guinea-pigs were starved and sweetened overnight before the experiment.

Cut 40 cm from 2 cm above the ileum and caecum junction to 37 ° C. Tyrode solution (mM) with 95% O ₂ /5% CO ₂ [NaCl 136.9, KCl 2.7, CaCl ₂ 1.8, MgCl ₂ 1.15, NaH ₂ PO ₄ 0.4, NaHCO ₃ 11.9, glucose 5.6]. Of these, 10 cm of the lower end of the ileum was used. The ileal muscles were cut to 1.5-2 cm and placed in a 50 ml organ bath containing 37 ° C. tie rod solution, and 95% O ₂ /5% CO ₂ was injected into the tie rod solution.

After stabilization for 1 hour, to observe two or three times bradykinin (1 u M) contractile response for every 20 minutes to measure the sensitivity and reproducibility of the contractile response meeting. Only reproducibility was confirmed during the meeting.

Prevent the degradation of bradykinin, and nerve activity was used as prostasin Glidden dithiothreitol, mercapto ruffle, atropine, of the tie rod each solution to block Dean generation 1 u M indomethacin was added shoes. The control group used saline instead of antagonist.

1) 0.1 u Determination of bradykinin antagonist activity at M concentration

After washing and stabilizing, each 0.1 u M of bradykinin antagonist prepared in Example 1 was added, and after 5 minutes, bradykinin was added. This experiment was performed at the same concentration (0.1 u M) in all libraries and individual materials.

The ileal contractile response was measured with a Grass model 76E polygraph, and the results are shown in Table 1 and Table 2.

sample % Inhibition sample % Inhibition pM3-H 29.40 pM8-H 29.40 pM4-H 52.38 pM10-H 54.54 pM5-H 28.00 pM11-H 33.33 pM6-H 57.69 pM12-H 27.27

sample % Inhibition sample % Inhibition pM1S1-5 12.3 ± 6.2 pM2S1-5 22.4 ± 5.9 pM1S3pM1S5 12.0014.00 pM2S2pM2S5 20.0016.66 pM3S1-5 32.0 ± 12.3 pM4S1-5 32.8 ± 15.2 pM3S1pM3S2pM3S3pM3S4pM3S5 52.6328.5742.8621.0520.00 pM4S3pM4S4pM4S5 45.4530.0023.53 pM5S1-5 28.8 ± 10.9 pM6S1-5 35.8 ± 11.2 pM5S1pM5S2pM5S3pM5S4 26.9028.7527.2728.57 pM6S1pM6S2 20.0021.05 pM7S1-5 6.3 ± 6.5 pM8S1-5 24.6 ± 17.7 pM7S1pM7S2pM7S5 6.389.622.13 pM8S1pM8S4pM8S5 10.0034.1821.75 pM9S1-5 9.0 ± 4.2 pM10S1-5 18.2 ± 10.3 pM9S3pM9S5 12.516.66 pM10S2 12.50

As shown in Table 1 and Table 2, the inhibitory effect of nitrogen-protected compounds (pM3-H ~ pM12-H) is 27.27 ~ 57.69%, library pM3S1-5 when showing an inhibitory effect of 32.01%, Individual substances pM3S1 ~ pM3S5 showed similar values with an average of 33.02%. In this case, the inhibitory effect of the library and individual substances on bradykinin was confirmed to be similar. Thus, by synthesizing using combinatorial chemistry, it contributes greatly to drug screening by precipitating only a specific library with good effect and identifying its individual substance.

On the other hand, the libraries pM4S1-5 and pM6S1-5 showed relatively higher bradykinin antagonistic effects than their individual substances. In this case, there seems to be a synergy between each individual substance. Thus, the presence of certain individual substances together increases their activity, indicating that the library exhibits higher than expected effects. Therefore, the combinatorial chemistry can be used to develop a more effective drug by combining one or more substances by finding a correlation between the drugs having a synergistic effect.

2) Determination of activity of bradykinin antagonist according to concentration

In addition, experiments were carried out with varying concentrations of bradykinin (1 nM to 3 u M) to determine the accumulation-response curves for bradykinin.

Three substances with relatively strong bradykinin antagonists were selected according to the pharmacological activity of the library and individual substances.

At the end of each curve, 80 mM KCl was added to confirm maximal response of the ileum. After washing and stabilizing, the activity was measured while changing the concentration of individual substances (0.03 u M-1.0 u M). Hoe140 was used as a control and the same experiment was carried out at 0.01 ~ 0.3 u M concentration.

The results are shown in FIGS. 3 to 6.

pM3S3 and pM4S3 decrease the maximum response to bradykinin (E _max ), but do not decrease the ED ₅₀ value, it can be seen that inhibits bradykinin non-competitively or indirectly.

In addition, pM6-H competitively inhibited bradykinin induced contraction, with an IC ₅₀ value of 1.09 × 10 ⁻⁶ M.

The novel non-peptide compounds having bradykinin antagonistic action of the present invention exhibit an antagonistic action on bradykinin receptors, resulting in the effect of preventing or treating various diseases mediated by bradykinin.

In addition, the method for preparing a compound of the present invention uses a liquid combinatorial chemistry method, which is effective in providing a large number of various compounds in a fast, efficient, infinite scale, high purity, and simple process.

Claims (9)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof. <Formula 1> In the general formula 1 R ¹ is isopropyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 1-methyl-3-phenylpropyl, 3,4,5-trimethoxy-benzyl, 2- (4- (4 -Chlorophenyl) thiazole), 3- (5-t-butylisoxazole), 2- (4- (4-bromophenyl) thiazole), cyclohexyl, 5- (3-methylisoxazole) and 3 , 4-benzyl refers to one member selected from the group consisting of oxy-phenethyl, R ² or R ³ is H CO, R ³ is methyl, a phenyl, benzyl, naphthyl (C ₁₀ H _7), and C ₁₀ H ₇ in CH ₂ represents one member selected from the group consisting. The method of claim 1, i) N- (4-methoxybenzyl) -N'-1- (4-chlorobenzylhydryl) piperazine iminodiacetic diamide, Ii) N- (3,4,5-trimethoxybenzyl) -N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic diamide, Iii) N-cyclohexyl-N'-1- (4-chlorobenzhydryl) piperazine iminodiacetic diamide, Iii) N-acetyl-N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide, Iii) N-phenylacetyl-N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide, V) N- (2-naphthoyl) -N '-(4-methylbenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiisacetic acid triamide and Iii) N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide One compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. delete Using a liquid phase combinatorial method, 1) forming iminodiacetic anhydride using imci in an in-situ reaction with iminodiacetic acid protected with nitrogen, and reacting with amines, 2 1) reacting 1- (4-chlorobenzhydryl) piperazine with the compound produced in 1), 3) removing the protecting group bound to nitrogen with hydrochloric acid and dioxane, and 4) compound produced in 3). A method for producing the compound of claim 1 or 2, comprising the step of bonding a carboxylic acid to the compound. The method according to claim 4, wherein the protecting group in step 1) is one selected from the group consisting of benzyl, benzyloxycarbonyl and t-butyloxycarbonyl groups. The method of claim 5, wherein the amines in step 1) are benzylamine, 4-methylbenzylamine, 4-methoxybenzylamine, 1-methyl-3-phenyl propylamine, 3,4,5-trimethoxybenzylamine, 2- (4- (4-chlorophenyl) thiazole) amine, 3- (5-t-butylisoxazole) amine, 2- (4- (4-bromophenyl) thiazol) amine, cyclohexylamine, It is 1 type chosen from the group which consists of 5- (3-methylisoxazole) amine and 3, 4- dibenzyloxy phenethylamine, The manufacturing method of the compound of Claim 1 or 2 characterized by the above-mentioned. The method according to claim 6, wherein the carboxylic acid in step 4) is one selected from the group consisting of acetic acid, benzoic acid, phenylacetic acid, 2-naphthoic acid and 2-naphthyl acetic acid. Method for preparing the compound. delete Claim 1 or 2 of the compound or a pharmaceutically acceptable salt thereof as an active ingredient, bradykinin-mediated asthma, allergic rhinitis, arthritis, shock, rheumatoid arthritis, cerebral edema, angioedema and acute A pharmaceutical composition used for the prevention or treatment of one disease selected from the group consisting of pancreatitis.